Fibroblast growth factor (FGF) is a peptidic cell growth factor which exhibits a growing action toward cells such as fibroblast and endothelial cells of blood vessels. Fibroblast growth factor is a general term for a family of several peptides mainly comprising basic FGF and acidic FGF. Acidic FGF (aFGF) is a protein with a molecular weight of about 16 kD comprising 140 amino acid residues. Acidic FGF is widely distributed in various tissues in living organisms. It is especially abundant in the brain and retina. Acidic FGF has been known to exhibit various physiological actions necessary for maintaining the homeostasis of a living body such as new growth of blood vessels due to cell growth action, curing of wounds, curing of ulcers and growth of undifferentiated osteogenic cells, as well as improvement of memory and control of appetite.
As mentioned above, aFGF is a protein having many useful physiological activities. However, organic synthesis of a peptide having as many as 140 amino acid residues requires many steps and operations. The organic synthesis is not economically feasible and, therefore, its use is not practical. Accordingly, gene recombination has been actually utilized but, to obtain a product of uniform quality, high technique is required. Also, unlike in the case of organic synthesis, special facilities are necessary. In addition, FGF has a low organ specificity and has a tendency to conduct neovascular action to give cancer cells. Therefore, its actual application as a pharmaceutical agent is still problematic whereby manufacture of its derivatives and a specific method for administration have been investigated. Further, it is a protein having a molecular weight of 16 kD and, when compared with other peptides having small sizes, there are problems such as antigenicity and incorporating an effective amount into the brain. Consequently, there are still several problems that have to be solved for its actual production as a pharmaceutical, or for meeting certain standards for use in an actual therapy.
There are some cases where, in achieving the activity of physiologically active high-molecular weight substances, the use of the total structure of the maturation protein is not always necessary. Thus, it has been known that even a partial fragment often exhibits the same physiological activity as the parent protein provided that said fragment contains the active moiety of the maturation protein. In addition, when a part of the amino acids participating in the active moiety of the peptide is substituted with other amino acids, it is possible to achieve reinforcement of biological activity, an increase in stability, elongation of duration or effectiveness, improvement in tissue specificity, improvement in incorporation into tissues, reduction of side effects, etc. of the peptide and its partial fragments. The present inventors have conducted investigations on partial peptides of aFGF which have various advantages such as the same physiological activity exhibited by aFGF but which are made by a simple and easy synthesis whereupon they have found the peptides of the present invention.
The peptide fragments of the present invention and their pharmaceutically acceptable salts have a relatively low molecular weight for incorporation into tissues and may be readily synthesized. They exhibit excellent physiological activity for improving cerebral functions and for protection of cerebral neurons.